Understanding the factors that control T cell responses has been a major focus of immunology. Despite this effort the factors that control T cell development, homeostasis and function are still only incompletely understood. Accordingly we have been studying the TNF-family cytokine BAFF (B cell activation factor of the TNF-family) in relation to T cell behaviour and function. Though BAFF was first described as being critical for B cell development and maturation, a number of lines of evidence ind ....Understanding the factors that control T cell responses has been a major focus of immunology. Despite this effort the factors that control T cell development, homeostasis and function are still only incompletely understood. Accordingly we have been studying the TNF-family cytokine BAFF (B cell activation factor of the TNF-family) in relation to T cell behaviour and function. Though BAFF was first described as being critical for B cell development and maturation, a number of lines of evidence indicate that BAFF may be important in T cell biology. Current studies suggest that BAFF exerts a pro-inflammatory effect upon T cell responses. Surprisingly then, when we examined the role of BAFF upon T cell function in vivo in the context of the allo-immune response, we found that ~60% of BAFF transgenic mice failed to reject a fully-mismatched allograft. Intriguingly, BAFF transgenic mice exhibited an increased number of CD4+ CD25+ Foxp3+ cells in the periphery and in vivo depletion of these CD25+ cells restored the ability of BAFF transgenic mice to reject an allograft. We hypothesize that BAFF plays a potentially powerful anti-inflammatory role in regulating certain T cell dependent immune responses. Our data suggests that BAFF can modulate T cell function by effecting T cell regulation.Read moreRead less
CD39 Protects Against Renal Ischaemic-reperfusion Injury
Funder
National Health and Medical Research Council
Funding Amount
$441,584.00
Summary
In many medical settings, such as heart attacks, strokes, transplantation, heart surgery, shock and infection, the blood supply to an organ may be compromised resulting in damage. The cessation of blood flow depletes the organ of oxygen and generates a number of toxic changes. Re-establishing blood flow to the organ is essential to prevent further damage, however the reestablishment of blood flow itself can be harmful to the organ. The return of blood flow, oxygen and energy can actually promote ....In many medical settings, such as heart attacks, strokes, transplantation, heart surgery, shock and infection, the blood supply to an organ may be compromised resulting in damage. The cessation of blood flow depletes the organ of oxygen and generates a number of toxic changes. Re-establishing blood flow to the organ is essential to prevent further damage, however the reestablishment of blood flow itself can be harmful to the organ. The return of blood flow, oxygen and energy can actually promote more widespread injury - a process known as ischaemia-reperfusion injury (IRI). A greater understanding of IRI should aid in the development of drugs that minimise its impact. The overall aim of this work is to examine the role of a molecule - CD39 - in IRI. This molecule is ideally situated to minimise injury - it is located on cells that line blood vessels and, as such, is able to directly neutralise toxins released in response to this injury. We, therefore, believe that it will be protective in this setting. We have developed animals that express this molecule and have preliminary results to suggest that these animals are protected in experimental models of IRI as well as in several other models including heart transplantation surgery; processes that share many features with IRI. Moreover, mice deplete of this molecule are prone to more severe IRI. We aim to investigate this by using animals both lacking and expressing CD39. Blood flow to the kidneys will be interrupted for 30 minutes and kidney function assessed at 24 and 48 hours. We will then delve into the potential mechanisms underpinning IRI by determining whether the kidney itself or the blood cells afford protection, which has direct clinical implications.Read moreRead less
Human cytomegalovirus (HCMV) is a classic example of a group of herpes viruses, which is found universally throughout all geographic locations and socioeconomic groups, and infects 50% of adults in developed countries. HCMV infection is important to certain high-risk groups. Major areas of concern are: (1) the risk of infection to unborn baby during pregnancy, (2) the risk of infection to people who work with children, and (3) the risk of infection to immunocompromised persons (e.g. organ transp ....Human cytomegalovirus (HCMV) is a classic example of a group of herpes viruses, which is found universally throughout all geographic locations and socioeconomic groups, and infects 50% of adults in developed countries. HCMV infection is important to certain high-risk groups. Major areas of concern are: (1) the risk of infection to unborn baby during pregnancy, (2) the risk of infection to people who work with children, and (3) the risk of infection to immunocompromised persons (e.g. organ transplant patients and HIV-infected individuals). Epidemiological studies have shown that 80%-90% of developing unborn babies who acquire congenital HCMV infection displays a variable pattern of pathological sequelae within the first few years of life that may include hearing loss, vision impairment and mental retardation. There is an increasing argument that a reduction in HCMV load will have a significant effect on the sequelae associated with congenital HCMV infection. Indeed, vaccination provides the most practical modality of achieving such a reduction in HCMV load. To develop such a vaccine, formulation based on viral antigens that activate both protective cellular and humoral responses needs to be tested to assess its immunogenicity. No such vaccine is presently available for HCMV. In this application we have sought to develop a prophylactic vaccine and to test its efficacy in a immunocompetent transgenic mouse model and as well under conditions of immunosuppression (CD4 T cell deficient). The overall strategy is to use this prophylactic vaccine to stimulate the cellular (CD8+ and CD4+ T cells) and humoral responses against multiple HCMV antigens. This vaccine will be based on the novel chimeric polyepitope technology and exploits a novel replication deficient adenovirus expression system which has recently been approved for human use.Read moreRead less